Carbon monoxide-validated four-week smoking abstinence from 167,487 treatment episodes among patients from 42 UK National Health Service Stop Smoking Services (1 April 2009, to 30 June 2011) showed smoking abstinence rates were higher with varenicline than combination nicotine replacement therapy (43.5% vs. 36.9%) but systematic variation in medication effect across clinical services and differences in predictors of outcome between medications resulted in a small mean advantage for varenicline (odds ratio, 1.080; 95% CI, 1.003–1.163; difference, 1.86%; 95% CI, 0.07%–3.67%; P = .04).